pharmacodynamics I Flashcards
pharmacodynamics is the study of _____
biochemical & physiological effects of drugs at the receptor level
&
the response produced due to drug-receptor interactions
the 3D arrangement of receptors is the result of _____
their primary, secondary, tertiary, & quaternary structures
5 binding forces involved in drug-receptor interactions (listed in order from strongest to weakest), which one is irreversible
-covalent bond (irreversible)
-ionic bond
-hydrogen bond
-hydrophobic interactions
-van der waals bond
what is a covalent bond
2 atoms share a pair of electrons
long-lasting, irreversible
what is an ionic bond
electrostatic attraction forces between charged ions
reversible
what is a hydrogen bond
a proton accepts an e- from a donor like O or N
reversible
what is a van der waals bond
attractive forces between nonpolar molecules
very weak
reversible
what are hydrophobic interactions
tendency of nonpolar molecules to interact w each other
important for lipid soluble drugs
reversible
what is an agonist
an agent that binds a receptor & produces a signal
what is an antagonist
an agent that binds a receptor & prevents the agonist from producing an effect
receptors mediate the actions of _____
agonists & antagonists
orthosteric site vs allosteric site
orthosteric site- where a drug binds if it’s the same site as the endogenous agonist
allosteric site- where a drug binds on a different region of the receptor
what is a primary agonist
drug that binds to the orthosteric site
what is an allosteric modulator
drug that binds to the allosteric site
4 receptor superfamilies
-ionotropic receptors
-metabotropic receptors
-enzyme-linked receptors
-intracellular receptors
ionotropic receptors
-structure
-binding site
-how they’re opened
receptors coupled to ion channels
-4-5 subunits surrounding central core
-binding site: large extracellular N-terminal
-opened via:
ligand, voltage, OR 2nd messenger regulated
metabotropic receptors
-structure
-binding site
indirectly coupled to G-proteins
-single polypeptide chain; 7 transmembrane alpha helices & 4 intracellular domains
-binding site: transmembrane helices
enzyme-linked receptors
-receptors for what
-where are the effects seen
-structure
-binding site
-receptors for growth factors, cytokines, insulin
-effects are exerted at gene transcription level
-only 1 helical transmembrane subunit
-binding site: extracellular N-terminus
intracellular receptors, type I
-what binds to them
-located where
have targets for sex hormones & glucocortioid
-located in cytoplasm, bound to hsp90
intracellular receptors, type II
-what binds to them
-located where
have targets for thyroid hormone, vitamin A & D, & retinoid
-located in nucleus
2 categories of mammalian G-proteins
heterotrimeric G-proteins
small G-proteins
when a ligand can bind many different _____ to produce specific effects
receptor subtypes
homologous desensitization mechanism (2 stages)
(agonist-dependent desensitization)
1) GRKs 1-7 phosph agonist-occupied GPCRs (1st stage can be reversed)
2) the phosph increases affinity for Arrestins to bind = maximal homologous desensitization (receptor can no longer bind G-protein & is endocytosed)
what does GRK stand for
G-protein coupled receptor kinase
heterologous desensitization mechanism
1) second messenger-dependent kinases (PKA, PKC) phosph both agonist-stimulated & non-stimulated GPCRs
(agonist-independent desensitization)
40-50% loss of receptor function
2 types of rapid desensitization that can occur for GPCRs (G-protein coupled receptors), & how do these occurs
homologous
heterologous
both occur via protein phosphorylation
PKA, PKC during heterologous desensitization phosph _____
sites different from GRKs
regulation of receptor function at receptor level
down-regulation
up-regulation
regulation of receptor function at post-receptor level
homologous / heterologous desensitization
what is down-regulation, relating to receptor-level regulation
persistent agonist stimulation by endogenous neurotransmitter / synthetic agonist
decrease in receptor number
what is up-regulation, relating to receptor-level regulation
chronic deprivation of receptor excitation by lack of endogenous neurotransmitter / persistent antagonist
increase in receptor number
another word for desensitization
tachyphylaxis
heterotrimeric G-proteins
alpha, beta, gamma subunits
alpha subunit = binds & hydrolyzes
beta, gamma subunits = hydrophobic, form a beta-gamma complex
small G-proteins
monomeric
belong to Ras superfamily of GTPases
heterogeneity of G-proteins allows _____
different receptors to exert opposite effects on a target enzyme
examples of metabotropic receptors
5-HT2
muscarinic M1
dopamine D2
exampls of ionotropic receptors
GABA a
5-HT3
6 examples of 2nd messengers for G-proteins
cAMP
cGMP
IP3
PIP2
DAG
Ca2+
3 examples of 3rd messengers for G-proteins
PKA
PKC
PKG
5 examples of intracellular targets of G-proteins
adenylyl cyclases (9 types)
guanylyl cyclases (2 types)
phospholipase C (13 types)
phospholipase A (A1, A2)
ion channels
serotonin receptors
5-HT
serotonin receptor whose activation causes anxiety
5-HT1A
serotonin receptor whose activation causes hallucinations / depression
5-HT2A
serotonin receptor whose activation causes vomiting
5-HT3
